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EP0472077A2 - Pseudopeptides du type hydroxyéthylamine ou norstatine ayant un substituant de phosphonate - Google Patents

Pseudopeptides du type hydroxyéthylamine ou norstatine ayant un substituant de phosphonate Download PDF

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Publication number
EP0472077A2
EP0472077A2 EP91113482A EP91113482A EP0472077A2 EP 0472077 A2 EP0472077 A2 EP 0472077A2 EP 91113482 A EP91113482 A EP 91113482A EP 91113482 A EP91113482 A EP 91113482A EP 0472077 A2 EP0472077 A2 EP 0472077A2
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
chain
straight
group
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91113482A
Other languages
German (de)
English (en)
Other versions
EP0472077A3 (en
Inventor
Dieter Dr. Häbich
Jutta Dr. Hansen
Arnold Dr. Paessens
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE4026703A external-priority patent/DE4026703A1/de
Priority claimed from DE4034707A external-priority patent/DE4034707A1/de
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0472077A2 publication Critical patent/EP0472077A2/fr
Publication of EP0472077A3 publication Critical patent/EP0472077A3/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D331/00—Heterocyclic compounds containing rings of less than five members, having one sulfur atom as the only ring hetero atom
    • C07D331/02—Three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to phosphonate-containing pseudopeptides of the hydroxyethylamine and norstatin type, new oxirane and thiirane-containing pseudopeptides as intermediates, processes for their preparation and their use as retroviral agents.
  • pseudopeptides some of which also have a renin-inhibitory effect, in combating AIDS [cf. GB A2 203 740; EP 337 714; EP 342 541; EP 346 847 and EP 352 000; EP 354 522; EP 356 223; EP 357 332; EP 337 714 and EP 357 332].
  • the compounds of the general formula (I) according to the invention have several asymmetric carbon atoms. They can exist independently of one another in the D or L form.
  • the invention includes the optical antipodes as well as the isomer mixtures or racemates. Groups A, B and D are preferably independently of one another in the optically pure, preferably in the L-form.
  • Amino protecting groups in the context of the invention are the usual amino protecting groups used in peptide chemistry.
  • benzyloxycarbonyl 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, meth Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, isobutoxycarbonyl, isobutoxycarbonyl, isobutoxycarbonyl, isobutoxycarbonyl
  • the compounds of the general formula (I) according to the invention can be present in the form of their salts. These can be salts with inorganic or organic acids or bases.
  • the customary inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps.
  • These preferably include organic solvents such as ethers, for example diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethylsulfoxide, dimethylformamide, hexamidylphidomidphidomethylphidomidphosphidylphidomethylphosphid , Triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, chloroform, dimethylformamide or tetrahydrofuran are particularly preferred.
  • the compounds of the general formula (II) are known per se and can be reacted by reacting a corresponding fragment, consisting of one or more amino acid groups, with a free, optionally in activated form, carboxyl group with a complementary fragment, consisting of one or more amino acid groups an amino group, optionally in activated form, and by repeating this process with appropriate fragments, then protective groups can optionally be split off or exchanged for other protective groups [cf. Houben-Weyl, Methods of Organic Chemistry, Synthesis of Peptides II, 4th Edition Vol. 15/1, 15/2, Georg Thieme Verlag, Stuttgart].
  • Condensation agents which can also be bases, are preferably used as auxiliaries for the respective peptide couplings and for the introduction of the radical W (III), (IV) and the phosphonate ring of the formula (VII), in particular if the carboxyl group is present as an anhydride.
  • the usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N ', are preferred here.
  • alkali carbonates e.g. Sodium or potassium carbonate or bicarbonate
  • organic bases such as trialkylamines e.g. Triethylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine
  • N-methylmorpholine is preferred.
  • auxiliaries and bases are used in an amount of 1.0 mol to 3.0 mol, preferably 1.0 to 1.2 mol, based in each case on 1 mol of the compounds of the general formulas (II), (III), (IV) , (VII) and (VIII) used.
  • the reactions are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.
  • the reactions can be carried out both under normal pressure and under increased or reduced pressure (for example 0.5 to 5 bar), preferably in the case of [A] and [C] under normal pressure and in the case [B] under increased pressure.
  • Compounds of the general formula (VIa) according to the invention also have several asymmetric carbon atoms. They can exist independently of one another in the D or L form.
  • the invention includes the optical antipodes as well as the isomer mixtures or racemates.
  • Groups A, B and D are preferably independently of one another in the optically pure, preferably in the L-form.
  • solvents for processes [D] and [E] are suitable as solvents for processes [D] and [E].
  • organic solvents such as ethers, for example diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as Benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, dichloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dichloroethane or chloroform are particularly preferred.
  • organic ammonium chlorides or bromides such as, for example, benzyltriethylammonium chloride or bromide, methyltrioctylammonium chloride, tetrabutylammonium bromide, tricaprylmethylammonium chloride (Aliquat 336) are used as auxiliaries. Benzyltriethylammonium chloride and bromide are preferred.
  • Suitable acids in the rearrangement are, for example, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or tetrafluoroboric acid. Trifluoroacetic acid is preferred.
  • the acid is used in an amount of 0.01 mol to 0.1 mol, preferably in catalytic amounts, based on 1 mol of the compound of the formula (X).
  • the epoxidation and rearrangement are carried out in a temperature range from -10 ° C to + 90 ° C, preferably from 0 ° C to + 60 ° C.
  • the reactions can be carried out both at normal pressure and at elevated or reduced pressure (for example 0.5 to 5 bar), preferably at normal pressure.
  • the reactions [F] and [G] are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.
  • the reactions [F] and [G] can be carried out either under normal pressure or under increased or reduced pressure (for example 0.5 to 5 bar), preferably under normal pressure.
  • the compounds of the general formula (XI) are known per se or can be prepared by a method known from the literature [cf. JR Luly et al., J. Org. Chem. 52 , (1987), 1487].
  • the compounds of the general formula (VIII) are known or can be prepared by customary methods [cf. DOS 3 825 242; EP 252 727; EP 244 084; US 4,599,198 and EP 266,950].
  • the compounds according to the invention showed activity in cell cultures infected with lentivirus. This could be shown using the example of the HIV virus.
  • the HIV test was carried out with minor modifications using the method of Pauwels et al. (Journal of Virological Methods 20 (1988) 309-321).
  • PBL normal human blood lymphocytes
  • RPMI 1640 20% fetal calf serum with phythema agglutinin (90 ⁇ g / ml) and interleukin-2 (40 U / m).
  • phythema agglutinin 90 ⁇ g / ml
  • interleukin-2 40 U / m
  • the virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium so that 1 ⁇ 105 cells per ml were set.
  • the cells infected in this way were pipetted into 1 ⁇ 104 cells / well into the wells of 96-well microtiter plates.
  • the first vertical row of the microtiter plate only contained growth medium and cells which had not been infected but had otherwise been treated exactly as described above (cell control).
  • the second vertical row of the microtiter plate received only HIV-infected cells (virus control) in growth medium.
  • the other wells contained the compounds according to the invention in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test compounds were diluted 10-fold in steps of two.
  • test batches were incubated at 37 ° C. until the untreated virus control showed the syncytia formation typical of HIV (between days 3 and 6 after infection), which was then evaluated microscopically.
  • the untreated virus control resulted in about 20 syncytia under these test conditions, while the untreated cell control showed no syncytia.
  • IC-50 values were determined as the concentration of the treated and infected cells at which 50% (approx. 10 syncytia) of the virus-induced syncytia were suppressed by the treatment with the compound according to the invention.
  • the compounds according to the invention protect HIV-infected cells from virus-induced cell destruction.
  • the compounds according to the invention are valuable active substances for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine.
  • Points 2, 3 and 4 from the indication area in human medicine are preferred.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formulas (I) and (VIa) or which consist of one or more active compounds of the formula (I) or (VIa), and Process for the preparation of these preparations.
  • the active compounds of the formulas (I) and (VIa) should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture .
  • the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
  • the active ingredient (s) of the formulas (I) and (VIa) in a total amount of from about 0.5 to about 500, preferably 5 to 100 mg / kg body weight per 24 hours, if necessary in the form of several single doses, to achieve the desired results.
  • a single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight.
  • reaction mixture was poured into 40 ml of water, washed with 50 ml of ethyl acetate, the aqueous phase was concentrated in vacuo to a volume of about 20 ml and onto a Lobar finished column / Merck-Lichroprep RP-8 (40-63 ⁇ m ) Size C loaded. It was eluted with water, which contained an increasing proportion of acetonitrile. The product-containing fractions were combined and freeze-dried. 1.67 g (47% of theory) of the title compound were obtained as a colorless lyophilisate.
  • the water phase was washed twice with 10 ml of ethyl acetate and then chromatographed on a Lobar finished column / Merck-Lichroprep RP-8 (40-63 ⁇ m) size B. It was eluted with water, which contained an increasing proportion of acetonitrile. The product-containing fractions were combined and freeze-dried. 58 mg (12% of theory) of the polar diastereomer were obtained.
  • a suspension of 345 mg (0.67 mmol) of the compound from Example IX, 8 mg (5 mol%) of benzyltriethylammonium chloride and 668 mg (1.35 mmol) of magnesium monoperoxyphthalate hexahydrate (MMPP) in 3 ml of chloroform was obtained by adding 1N NaOH -Solution adjusted to pH 5 and heated to reflux for 16 h, keeping pH about 5 by adding small amounts of 1N NaOH. After cooling, the reaction mixture was filtered off and the filtrate was washed with 10 ml of water, 10 ml of 10% Na2SO3 solution and 10 ml of dilute NaHCO3 solution and dried over magnesium sulfate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyridine Compounds (AREA)
EP19910113482 1990-08-24 1991-08-12 Phosphonate containing hydroxyethylamin- and norstatin-type pseudopeptides Withdrawn EP0472077A3 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE4026703A DE4026703A1 (de) 1990-08-24 1990-08-24 Phosphonat-haltige pseudopeptide vom hydroxyethylamin- und norstatin-typ
DE4026703 1990-08-24
DE4034707A DE4034707A1 (de) 1990-11-01 1990-11-01 Oxiran- und thiiran-haltige pseudopeptide
DE4034707 1990-11-01

Publications (2)

Publication Number Publication Date
EP0472077A2 true EP0472077A2 (fr) 1992-02-26
EP0472077A3 EP0472077A3 (en) 1993-03-31

Family

ID=25896164

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910113482 Withdrawn EP0472077A3 (en) 1990-08-24 1991-08-12 Phosphonate containing hydroxyethylamin- and norstatin-type pseudopeptides

Country Status (11)

Country Link
US (1) US5364931A (fr)
EP (1) EP0472077A3 (fr)
JP (1) JPH04257597A (fr)
KR (1) KR920004411A (fr)
AU (1) AU640262B2 (fr)
CA (1) CA2049645A1 (fr)
HU (1) HUT59695A (fr)
IE (1) IE912996A1 (fr)
IL (1) IL99251A0 (fr)
NZ (1) NZ239493A (fr)
PT (1) PT98741A (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015956A1 (fr) * 1993-01-04 1994-07-21 The Wellcome Foundation Limited Inhibiteurs de l'enzyme transformant l'endotheline
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
WO2002080921A1 (fr) * 2001-04-09 2002-10-17 Republic Of Korea Composition permettant d'inhiber l'activite de vih contenant un extrait de paecilomyces sp. (tochu-kaso) j300
EP1447398A1 (fr) * 1992-05-21 2004-08-18 Monsanto Company Inhibiteurs de protéase rétrovirale
US11952365B2 (en) 2020-06-10 2024-04-09 Aligos Therapeutics, Inc. Anti-viral compounds
US12036286B2 (en) 2021-03-18 2024-07-16 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds
US12065428B2 (en) 2021-09-17 2024-08-20 Aligos Therapeutics, Inc. Anti-viral compounds
US12252481B2 (en) 2021-07-09 2025-03-18 Aligos Therapeutics, Inc. Anti-viral compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3396507B2 (ja) * 1993-05-12 2003-04-14 株式会社東芝 Ｍｒ撮像方法および磁気共鳴イメージング装置

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186268A (en) * 1979-01-29 1980-01-29 E. R. Squibb & Sons, Inc. Mercaptoacylpyrrolidine phosphonic acids and related compounds
JPS61183297A (ja) * 1985-02-08 1986-08-15 Suntory Ltd プロリンエンドペプチダ−ゼインヒビタ−活性を有する新規ペプチド化合物
DE3824669A1 (de) * 1988-07-20 1990-01-25 Wondrak Ewald M Mittel zur praevention vor infektion mit hiv

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599198A (en) * 1985-08-02 1986-07-08 Pfizer Inc. Intermediates in polypeptide synthesis
DE4026614A1 (de) * 1990-08-23 1992-02-27 Bayer Ag Phosphonopyrrolidin- und piperidin-haltige pseudopeptide vom statintyp, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel gegen retroviren

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186268A (en) * 1979-01-29 1980-01-29 E. R. Squibb & Sons, Inc. Mercaptoacylpyrrolidine phosphonic acids and related compounds
JPS61183297A (ja) * 1985-02-08 1986-08-15 Suntory Ltd プロリンエンドペプチダ−ゼインヒビタ−活性を有する新規ペプチド化合物
DE3824669A1 (de) * 1988-07-20 1990-01-25 Wondrak Ewald M Mittel zur praevention vor infektion mit hiv

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY Bd. 31, Nr. 3, 1988, WASHINGTON, USA Seiten 532 - 539 LULY ET AL 'New inhibitors of human renin that contain novel Leu-Val replacements. Examination of the P1 site' *
PATENT ABSTRACTS OF JAPAN vol. 11, no. 3 (C-395)(2450) Januar 1987 & JP-A-61 183 297 ( SUNTORY LTD. ) 15. August 1986 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1447398A1 (fr) * 1992-05-21 2004-08-18 Monsanto Company Inhibiteurs de protéase rétrovirale
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5760036A (en) * 1992-07-20 1998-06-02 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5776933A (en) * 1992-07-20 1998-07-07 E. R. Squibb & Sons, Inc. Method of inhibiting protease
EP1029869A1 (fr) * 1993-01-04 2000-08-23 The Wellcome Foundation Limited Inhibiteurs de l'enzyme transformant l'endotheline
US6235717B1 (en) 1993-01-04 2001-05-22 Glaxo Wellcome Inc. Pharmaceutical compounds
WO1994015956A1 (fr) * 1993-01-04 1994-07-21 The Wellcome Foundation Limited Inhibiteurs de l'enzyme transformant l'endotheline
WO2002080921A1 (fr) * 2001-04-09 2002-10-17 Republic Of Korea Composition permettant d'inhiber l'activite de vih contenant un extrait de paecilomyces sp. (tochu-kaso) j300
US7704957B2 (en) 2001-04-09 2010-04-27 Rural Development Administration Composition for inhibiting HIV activity extracted from Paecilomyces sp. (Tochu-kaso) J300
US11952365B2 (en) 2020-06-10 2024-04-09 Aligos Therapeutics, Inc. Anti-viral compounds
US12036286B2 (en) 2021-03-18 2024-07-16 Seagen Inc. Selective drug release from internalized conjugates of biologically active compounds
US12252481B2 (en) 2021-07-09 2025-03-18 Aligos Therapeutics, Inc. Anti-viral compounds
US12065428B2 (en) 2021-09-17 2024-08-20 Aligos Therapeutics, Inc. Anti-viral compounds

Also Published As

Publication number Publication date
AU8266591A (en) 1992-02-27
AU640262B2 (en) 1993-08-19
EP0472077A3 (en) 1993-03-31
NZ239493A (en) 1993-10-26
IE912996A1 (en) 1992-02-26
US5364931A (en) 1994-11-15
KR920004411A (ko) 1992-03-27
JPH04257597A (ja) 1992-09-11
PT98741A (pt) 1992-07-31
HU912778D0 (en) 1992-01-28
IL99251A0 (en) 1992-07-15
HUT59695A (en) 1992-06-29
CA2049645A1 (fr) 1992-02-25

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